Predictive Value of Combining Biomarkers for Clinical Outcomes in Advanced Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors.

INTRODUCTION: A high tumor mutational burden (TMB) (≥10 mut/Mb) has been associated with improved clinical benefit in non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI) and is a tumor agnostic indication for pembrolizumab across tumor types. We explored whether combining TMB with programmed cell death ligand 1 (PD-L1) and pretreatment neutrophil-lymphocyte ratio (NLR) was associated with improved outcomes in ICI-treated NSCLC. METHODS: We retrospectively analyzed patients treated with ICI with Foundation One genomic testing, including TMB. Optimal cutoff for prediction of response by TMB was determined by receiver operating characteristic analysis, and area under the curve (AUC) was calculated for all 3 biomarkers and combinations. Cox model was used to assess prognostic factors of overall survival (OS) and time to progression (TTP). Survival cutoffs calculated with Kaplan-Meier survival curves were TMB ≥10 mut/Mb, PD-L1 ≥50%, NLR <5, and combined biomarkers. RESULTS: Data from 88 patients treated were analyzed. The optimal TMB cutoff was 9.24 mut/Mb (AUC, 0.62), improving to 0.74 combining all 3 biomarkers. Adjusted Cox model showed that TMB ≥10 mut/Mb was an independent factor of OS (hazard ratio [HR], 0.31; 95% confidence interval; 0.14-0.69; P = .004) and TTP (HR, 0.46; 95% CI, 0.27-0.77; P = .003). The combination of high TMB with positive PD-L1 and low NLR was significantly associated with OS (P = .038) but not TTP. CONCLUSIONS: TMB has modest predictive and prognostic power for clinical outcomes after ICI treatment. The combination of TMB, PD-L1, and NLR status improves this power.

Novel therapies are changing treatment paradigms in metastatic prostate cancer.

Metastatic castration-resistant prostate cancer (mCRPC) remains a terminal diagnosis with an aggressive disease course despite currently approved therapeutics. The recent successful development of poly ADP-ribose polymerase (PARP) inhibitors for patients with mCRPC and mutations in DNA damage repair genes has added to the treatment armamentarium and improved personalized treatments for prostate cancer. Other promising therapeutic agents currently in clinical development include the radiotherapeutic 177-lutetium-prostate-specific membrane antigen (PSMA)-617 targeting PSMA-expressing prostate cancer and combinations of immunotherapy with currently effective treatment options for prostate cancer. Herein, we have highlighted the progress in systemic treatments for mCRPC and the promising agents currently in ongoing clinical trials.

Practical Successes in Telepathology Experiences in Africa.

Across much of Africa, there is a critical shortage of pathology services necessary for clinical care. Even in settings where specialty-level clinical care, such as medical oncology, is available, access to anatomic pathology services has often lagged behind. Pathology laboratories in the region are challenging to establish and maintain. This article describes the successful implementation of telepathology services in Malawi and reviews other successful programs developed to support diagnostic pathology in resource-limited settings.

Lymphoma and Pathology in Sub-Saharan Africa: Current Approaches and Future Directions.

The care of patients with lymphoma relies heavily on accurate tissue diagnosis and classification. In sub-Saharan Africa, where lymphoma burden is increasing because of population growth, aging, and continued epidemic levels of human immunodeficiency virus infection, diagnostic pathology services are limited. This article summarizes lymphoma epidemiology, current diagnostic capacity, and obstacles and opportunities for improving practice in the region.

Extranodal natural killer/T-cell lymphoma in Malawi: a report of three cases.

BACKGROUND: Extranodal NK/T-cell lymphoma (ENKTCL) reports from sub-Saharan Africa (SSA) are remarkably rare, despite early childhood acquisition and high prevalence of the causative infectious agent, Epstein-Barr virus (EBV), and frequent occurrence of other lymphoproliferative disorders causally associated with EBV. CASE PRESENTATIONS: At a national teaching hospital in Malawi, three patients of African descent were seen with ENKTCL between 2013 and 2014. Patients were aged between 29 and 60 years, two with craniofacial involvement and one with a primary abdominal tumor, and all were HIV-negative. All had systemic B symptoms, and two severely impaired performance status. On histologic review, morphology and immunophenotyping demonstrated classical ENKTCL features in all cases, including diffuse proliferations of intermediate-to-large atypical lymphocytes with high mitotic activity and extensive background necrosis, positivity for CD3 and CD56, and negativity for CD20. By in situ hybridization, all three tumors were positive for EBV-encoded RNA (EBER). Baseline plasma EBV DNA was also markedly elevated for all three patients. Due to radiotherapy and chemotherapy limitations, patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) with rapid disease progression. All three patients died from progressive lymphoma within 3 months of initial diagnosis. CONCLUSIONS: Our experience with these three patients in Malawi can highlight that ENKTCL does indeed occur in SSA, increase familiarity with ENKTCL among clinicians and pathologists throughout the region, and emphasize the need for better diagnosis and treatment for this neglected population.

Advances in transcatheter valve therapies.

The surgical treatment for valvular heart disease is well established with excellent long-term outcomes in appropriately selected patients. For patients at elevated risk for surgical intervention, options have traditionally been limited to medical therapy with disappointing results. The advent of transcatheter techniques of valvular repair or replacement has revolutionized treatment options for these patients at significantly elevated risk for surgery. In both the aortic and mitral realms, landmark clinical trials and real-world registries have begun to define the roles of these therapies, and the development of multidisciplinary heart teams have helped optimize patient treatment pathways and outcomes. Transcatheter treatment of aortic stenosis and mitral regurgitation has emerged as an approved option for properly selected patients, and guidelines have evolved to include these therapies. Further procedural refinement, device development, and clinical trials will continue to evolve this field.

Left ventricular end-diastolic pressure affects measurement of fractional flow reserve.

BACKGROUND: Fractional flow reserve (FFR), the hyperemic ratio of distal (Pd) to proximal (Pa) coronary pressure, is used to identify the need for coronary revascularization. Changes in left ventricular end-diastolic pressure (LVEDP) might affect measurements of FFR. METHODS AND MATERIALS: LVEDP was recorded simultaneously with Pd and Pa during conventional FFR measurement as well as during additional infusion of nitroprusside. The relationship between LVEDP, Pa, and FFR was assessed using linear mixed models. RESULTS: Prospectively collected data for 528 cardiac cycles from 20 coronary arteries in 17 patients were analyzed. Baseline median Pa, Pd, FFR, and LVEDP were 73 mmHg, 49 mmHg, 0.69, and 18 mmHg, respectively. FFR<0.80 was present in 14 arteries (70%). With nitroprusside median Pa, Pd, FFR, and LVEDP were 61 mmHg, 42 mmHg, 0.68, and 12 mmHg, respectively. In a multivariable model for the entire population LVEDP was positively associated with FFR such that FFR increased by 0.008 for every 1-mmHg increase in LVEDP (beta=0.008; P<0.001), an association that was greater in obstructed arteries with FFR<0.80 (beta=0.01; P<0.001). Pa did not directly affect FFR in the multivariable model, but an interaction between LVEDP and Pa determined that LVEDP's effect on FFR is greater at lower Pa. CONCLUSIONS: LVEDP was positively associated with FFR. The association was greater in obstructive disease (FFR<0.80) and at lower Pa. These findings have implications for the use of FFR to guide revascularization in patients with heart failure. SUMMARY FOR ANNOTATED TABLE OF CONTENTS: The impact of left ventricular diastolic pressure on measurement of fractional flow reserve (FFR) is not well described. We present a hemodynamic study of the issue, concluding that increasing left ventricular diastolic pressure can increase measurements of FFR, particularly in patients with FFR<0.80 and lower blood pressure.

Comparison between angiography and fractional flow reserve versus single-photon emission computed tomographic myocardial perfusion imaging for determining lesion significance in patients with multivessel coronary disease.

We hypothesized that myocardial perfusion imaging (MPI) would fail to identify all vascular zones with the potential for myocardial ischemia in patients with multivessel coronary disease (MVD). MPI is based on the concept of relative flow reserve. The ability of these techniques to determine the significance of a particular stenosis in the setting of MVD is questionable. Fractional flow reserve (FFR) can determine the significance of individual stenoses. Thirty-six patients with disease involving 88 arteries underwent angiography, FFR, and MPI. FFR was performed using a pressure wire with hyperemia from intracoronary adenosine. Myocardial perfusion images were analyzed quantitatively and segments assigned to a specific coronary artery. The relation between FFR and perfusion was determined for each vascular zone. Of the 88 vessels, the artery was occluded (n=20) or had an abnormal FFR

Prevalence of unfavorable angiographic characteristics for percutaneous intervention in patients with unprotected left main coronary artery disease.

OBJECTIVES: The goal of this study was to determine the proportion of patients with left main coronary disease (LMCD) with unfavorable characteristics for percutaneous coronary intervention (PCI). BACKGROUND: Published series suggest that LMCD can be treated percutaneously, however, the proportion of patients in whom PCI is an option based on angiographic criteria is unknown. METHODS: In 13,228 consecutive coronary angiograms, 476 (3.6%) patients had < or =60% stenosis of the left main. In 232 patients with unprotected LMCD, the clinical characteristics and angiograms were reviewed with six features chosen as "unfavorable" for PCI: (1) Bifurcation LMCD, (2) occlusion of a major coronary, (3) ejection fraction <30%, (4) occlusion of a dominant RCA, (5) left dominant circulation, and (6) coexisting three-vessel disease. Treatment modality and 1 year mortality were determined. RESULTS: The mean age was 69 years and 68% were male. Unfavorable characteristics were common with at least one unfavorable characteristic seen in 80%. Bifurcation disease was the most common unfavorable characteristic observed (53%) and coexisting three-vessel disease was seen in 38%. Treatment consisted of CABG in 205 (88%), medical therapy in 24 (10%) and PCI in 3 (1%). Among patients referred for CABG, 1 year survival was 88% with similar rates of survival for those with favorable characteristics (86%) compared to those with at least one unfavorable characteristic (88%). CONCLUSIONS: Most patients with LMCD have at least one unfavorable characteristic for PCI suggesting that PCI may be a technically difficult option for most patients with LMCD.

Improvement in microvascular reflow and reduction of infarct size with adenosine in patients undergoing primary coronary stenting.

The aim of this study was to use myocardial contrast echocardiography to evaluate the effect of intravenous adenosine on microvascular reflow in patients with acute myocardial infarction who underwent primary coronary stenting (PCS). Thirty patients who underwent primary PCS for acute myocardial infarction were randomized to intravenous adenosine (50 to 70 mug/kg/min) or vehicle for 3 hours. Myocardial contrast echocardiography was performed before and sequentially after PCS to determine the risk area during coronary occlusion and infarct size. The risk area was similar in the adenosine- and placebo-treated patients. The infarct size as a ratio to the risk area was smaller in patients treated with adenosine when measured at 3 to 5 days (0.37 +/- 0.29 vs 0.68 +/- 0.25, p <0.01) and at 4 weeks (0.34 +/- 0.26 vs 0.60 +/- 0.21, p <0.01) after PCS. This effect was greatest when patency was achieved <4 hours after symptom onset (0.18 +/- 0.18 vs 0.74 +/- 0.31, p <0.05), with little effect after 4 hours. The relative microvascular blood volume in the risk area at 4 weeks was higher in patients receiving adenosine than in those receiving placebo (0.73 +/- 0.22 vs 0.57 +/- 0.20, p <0.01), and was highest when patency was achieved in <4 hours. In conclusion, the adjunctive use of intravenous adenosine after PCS reduces the infarct size relative to the risk area. This beneficial effect occurs primarily in those undergoing early intervention.

Electromechanical mapping identifies improvement in function and retention of contractile reserve after revascularization in ischemic cardiomyopathy.

BACKGROUND: We hypothesized that (1) a significant proportion of ischemic dysfunctional segments that do not improve function will demonstrate postrevascularization contractile reserve and (2) electromechanical mapping (EMM) can identify segments that improve function as well as those with postrevascularization contractile reserve, a potential indicator of delayed functional improvement. METHODS AND RESULTS: Eighteen patients with severe ischemic left ventricular dysfunction underwent EMM and dobutamine (D) cardiac magnetic resonance imaging (CMR) followed by revascularization. Four months after revascularization, all patients underwent a repeated D-CMR, and at 35 months, a subgroup (n=6) underwent a third CMR. Of 120 dysfunctional segments, 60 segments had improved rest function (IRF) and 60 did not. Twenty-eight of 60 segments (47%) that did not improve RF demonstrated postrevascularization contractile reserve (CR), and 32 of 60 segments (53%) that demonstrated neither IRF nor CR were persistently dysfunctional (PD). CR segments recovered significantly greater late function compared with IRF or PD: 14+/-12% vs 2+/-5% and 4+/-7%, respectively; P<0.05. EMM ratio, defined as the unipolar voltage divided by linear shortening, was significantly higher in IRF segments compared with segments that did not improve RF: 2.4+/-4.5 vs 0.7+/-3.5, P<0.05. Unipolar voltage was stepwise lower in normal, IRF, CR, and PD segments (10.5+/-4.7, 9.3+/-3.9, 8.8+/-3.2, and 7.4+/-2.3 mV, respectively; P<0.01 for trend). CONCLUSIONS: Almost half of dysfunctional myocardial segments in chronic ischemic heart disease that do not improve RF early after revascularization demonstrate early CR and delayed functional recovery. EMM parameters can identify segments that improve RF and retain CR early after revascularization.